Still another aspect of the invention relates to a method of inhibiting the action of enkephalinase in a mammal thereby to elicit an analgesic effect with a mercapto-acylamino compound of this invention. Analgesic pharmaceutical compositions comprising said mercapto-acylamino compounds are also contemplated.
Human hypertension represents a disease of multiple etiologies. Included among these is a sodium and volume dependent low renin form of hypertension. Drugs that act to control one aspect of hypertension will not necessarily be effective in controlling another.
Enkephalin is a natural opiate receptor agonist which is known to produce a profound analgesia when injected into the brain ventricle of rats. If is also known in the art that enkephalin is acted upon by a group of enzymes known generically an enkephalinases, which are also naturally occurring, and is inactivated thereby.
A variety of mercapto-acylamino acids are known as enkephalinase inhibitors useful as analgesics and in the treatment of hypertension.
U.S. Pat. No. 4,513,009 to Roques et al. discloses, inter alia, compounds of the formula. ##STR1## wherein n is 0 to 1; R.sup.1 includes hydrogen, optionally substituted alkyl, optionally substituted phenyl, cyclohexyl and thienyl; and R.sup.2 includes hydrogen optionally substituted alkyl, optionally substituted benzyl, phenyl, phenoxyalkyl and optionally substituted mercaptoalkyl. The compounds are disclosed as principally having enkephalinase activity, but also are said to be antihypertensives an analgesic.
U.S. Pat. No. 4,401,677 to Greenburg et al. and EPA 38,046 and Wilkinson disclose compounds of a scope similar to Roques et al, the former disclosing analgesic activity and the latter disclosing a greater specificity for enkephalinase than ACE. U.S. Pat. No. 4,053,651 to Ondetti et al. discloses the use of similar compounds in the treatment of renin-angiotensin related hypertension.
It has recently been discovered that the heart secretes a series of peptide hormones called atrial natriuretic factors (ANF) which help to regulate blood pressure, blood volume and the excretion of water, sodium and potassium. ANF were found to produce a short-term reduction in blood pressure and to be useful in the treatment of congestive heart failure. See P. Needleman et al., "Atriopeptin: A Cardiac Hormone Intimately Involved in Fluid, Electrolyte and Blood-Pressure Homeostasis", N. Engl. J. Med., 314, 13 (1986) pp. 828- 834, and M. Cantin et al in "The Heart as an Endocrine Gland", Scientific American, 254 (1986) pg, 76-81.
A class of drugs known to be effective in treating some types of hypertension is ACE inhibitors, which compounds are useful in blocking the rise in blood pressure caused by increases in vascular resistance and fluid volume due to the formation of angiotensin II from angiotensin I. For a review of ACE inhibitors, see M. Wyvratt and A. Patchett, "Recent Developments in the Design of Angiotensin Converting Enzyme Inhibitors" in Med. Res. Rev. Vol. 5, No. 4 (1985) pp. 483-531.